Current medicinal chemistry最新文献

Introduction: Parkinson's disease (PD) is a neurodegenerative disorder associated with a progressive loss of dopaminergic cells and as of now, there is no established definitive treatment available for this condition.

Method: In this study, the focus was on investigating the impact of SVAK-12, a small molecule that can cross the blood-brain barrier and remain stable without structural changes. The effect of SVAK-12 was investigated in vitro on neurotoxicity, in vivo model of Parkinson's Diseases and in silico.

Result: Through in vitro and in vivo experiments, as well as molecular docking simulations, it was found that SVAK-12 (375 ng.ml) led to increased cell viability, reduced cellular damage, and decreased production of NO and ROS. Additionally, it boosted levels of important neurotrophic factors like BDNF (130.49%) and GDNF (116.38%), potentially aiding in alleviating motor disability and depression. The study also highlighted SVAK-12's potential as a therapeutic candidate for neurological disorders due to its ability to increase tyrosine hydroxylase expression and dopamine levels (4.84 times). While it did not significantly improve motor symptoms in vivo, it did enhance motor asymmetry in the forelimbs and gene expression related to brain regions. Besides, it induced significant BMP-2 gene expression in substantial nigra regions without significant changes in GDNF and Nurr1 gene expression in the striatum expression. The docking of SVAK-12, Levodopa, Amantadine, Biperiden, Selegiline, and Rasagiline to the binding site of GFRα1, sortilin, and TrkB showed that SVAK-12 had greater MolDock score than Selegiline and Amantadine for GFRα1 and greater than amantadine for Sortilin and TrKB.

Conclusion: Overall, the study suggests that SVAK-12's neuro-biocompatibility, ability to reduce free radicals, and enhanced neurotrophic factors make it a promising candidate as a neuroprotective drug.

Background: PANoptosis plays an important role in many inflammatory diseases. However, there are no reports on the association between PANoptosis and CD.

Materials and methods: This study used five machine learning algorithms - least absolute shrinkage and selection operator, support vector machine, random forest, decision tree and Gaussian mixture models - to construct CD's PANoptosis signature. Unsupervised hierarchical clustering analysis was used to identify PANoptosis-associated subgroups of CD. Gene Ontology (GO) enrichment analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis, Gene Set Enrichment Analysis (GSEA) and Gene Set Variation Analysis (GSVA) were conducted to compare the PANoptosis-associated subgroups of CD among the potential biological mechanisms. Single sample GSEA was used to assess immune microenvironmental differences among the subgroups. The potential role of PANoptosis in CD was further explored using single-cell RNA-Seq (scRNA-Seq) for PANoptosis scoring, differential analysis, pseudotime analysis, cellular communication analysis and weighted gene co-expression network analysis (WGCNA) analysis.

Results: CD's PANoptosis signature consisted of seven genes: CEACAM6, CHP2, PIK3R1, CASP10, PSMB1, PSMB8 and UBC. The PANoptosis signature in multiple cohorts had a strong ability to recognise CD. The levels of immune cell infiltration and the vigour of the immune responses significantly varied between the two subpopulations of CD associated with PANoptosis. Multiple lines of evidence from the GO, KEGG, GSEA, GSVA, scRNA-Seq and WGCNA analyses suggested that I-kappaB kinase/NF- kappaB signalling, mitogen-activated protein kinase (MAPK), leukocyte activation and leukocyte migration were mechanisms closely associated with PANoptosis in CD.

Conclusion: This study is the first to construct a PANoptosis signature with excellent efficacy in recognising CD. PANoptosis may mediate the process of CD through inflammatory and immune mechanisms, such as NF- kappaB, MAPK and leukocyte migration.

Cyclodextrin Metal-Organic Frameworks (CD MOFs) represent an innovative class of materials with remarkable properties and a broad range of applications. This review provides a comprehensive overview of the synthesis techniques, structural characterization, and diverse applications of CD-MOFs. By combining cyclodextrins (CDs) with metal-organic frameworks (MOFs), CD-MOFs are developed with enhanced functionality. The synthesis methods, including various metal sources, coordination modes, and post-synthesis modifications, are discussed alongside advanced structural characterization techniques like X-ray crystallography and spectroscopic methods. The unique characteristics of CD-MOFs, such as high specific surface area, tunable porosity, and customizable chemical structure, make them exceptional candidates for applications in gas adsorption, drug delivery, catalysis, sensing, and environmental remediation. Notably, CD-MOFs show significant promise as nanocarriers in drug delivery systems, offering improved therapeutic outcomes due to their efficient encapsulation and controlled release capabilities. The review highlights recent advancements and underscores the potential impact of CD-MOFs in driving future innovations across various scientific fields.

Introduction: Alzheimer's disease (AD) is the most common neurodegenerative disease in older people, characterized by the accumulation of beta-amyloid (Aβ) plaques and neurofibrillary tangles composed of aggregated of hyperphosphorylated tau protein, which normally helps stabilize microtubules in neurons.

Method: Nowadays, artemisinin (ART) as well as its semisynthetic derivatives (ARTs) are seen as potential neuroprotectors. The goal of the present study is the assessment of neuroprotective, antibacterial activity of ART, as well as in silico studies of ART affinity to Aβ-peptides and the search of potential targets for ART. The study is referring to explores the impact of ART on an animal model of AD that is induced by the aggregated amyloidogenic peptide Aβ1-42 by electrophysiology and morphology analysis. Specifically, the focus is on the activation of the entorhinal cortex (ENT) as synaptic potentiation.

Result: Electrophysiological and histochemical have demonstrated that therapeutic injection of ART or its derivatives acts as a neuroprotective This treatment appears to prevent or slow down damage to brain tissue, and it promotes the restoration of neurons and their surrounding environment. The protective effects of ART may involve various mechanisms, including antioxidant activity, anti-inflammatory effects, and the inhibition of apoptosis.

Conclusion: in silico studies revealed a direct, strong interaction of ART with the amyloidogenic peptides 5Aβ17-42, 12Aβ9-40, and 18Aβ9-40. in silico screening revealed several protein targets for ART, including cytochrome P-450 2B6 (CYP2B6). The highest binding affinity was found on the active site of CYP2B6. ART has great potential for discovering new drugs using combined therapies.

Background: The role of Myocyte Enhancer Factor 2 C (MEF2C) in lung adenocarcinoma (LUAD) is unclear.

Objective: To address this gap in knowledge, we employed bioinformatics analysis and experimental validation in this study.

Methods: This study investigated MEF2C expression across a spectrum of cancers, with a specific focus on lung adenocarcinoma (LUAD), utilizing Cancer Genome Atlas (TCGA) data to assess its potential as a diagnostic marker. The study also investigated correlations between MEF2C expression and clinical traits and prognostic indicators of LUAD. Additionally, this study also delved into the regulatory mechanisms of MEF2C, examining its connections to immune system interactions, immune checkpoint genes, tumor mutational burden (TMB), and the sensitivity of LUAD to various drugs. Through single-cell sequencing of LUAD cells and genetic variation of MEF2C in LUAD, we explored the expression of MEF2C in cell lines and verified it by quantitative real-time PCR (qRT-PCR).

Results: MEF2C exhibited aberrant expression in both pan-cancer and LUAD. In individuals with LUAD, diminished levels of MEF2C expression were notably linked to the effectiveness of primary therapy outcome (p = 0.025), gender (p < 0.001), and the subdivision of anatomic neoplasms 2 (p = 0.011). A decline in MEF2C levels was also found to be significantly related to reduced overall survival (OS) in LUAD patients (p = 0.026). The presence of MEF2C was recognized as a standalone factor predictive of prognosis in LUAD (p = 0.029). MEF2C was found to be involved in multiple biological pathways, such as those involving cell adhesion molecules. Additionally, its expression was correlated with the extent of immune cell presence, the activity of immune checkpoint genes, and TMB in LUAD. Notably, an inverse relationship was observed between MEF2C expression and the sensitivity to several agents, including Topotecan, Irinotecan, Panobinostat, Nilotinib, and Tp38-279, within the context of LUAD. Furthermore, MEF2C was found to be significantly negatively regulated in LUAD cell lines.

Conclusion: The results imply that MEF2C could be a valuable indicator for predicting outcomes and a possible target for immunotherapy for LUAD patients.

Polycystic Ovary Syndrome (PCOS) is a common endocrinological disorder that affects women of reproductive age and can lead to infertility. The prevalence of PCOS ranges from 5-21% depending on the diagnostic criteria and study population. Clinical manifestations include irregular or absent menstrual periods, obesity, and signs of hyperandrogenism. PCOS can also lead to long-term consequences such as metabolic syndrome, increased risk of cardiovascular diseases, endometrial cancer, diabetes mellitus, and hypertension. Metformin and oral contraceptive pills are the most commonly used drugs for PCOS management, but their efficiency is limited and they have some considerable side effects. Researchers are looking into alternative therapeutic options such as phytochemicals. Curcumin (CUR) is a polyphenolic compound found in the rhizome of Curcuma longa and has shown promising effects for females with PCOS. CUR exerts its anti-PCOS effects through different mechanisms such as reducing oxidative stress and inflammation, balancing hormone levels, and controlling the blood sugar and lipid profile. It can also reduce insulin resistance, regulate menstruation, and improve ovarian morphology and function. Despite its beneficial effects, CUR faces several challenges and limitations in clinical use, such as low bioavailability, instability, and rapid elimination. Therefore, researchers are investigating the potential of CUR nanoformulations and new drug delivery systems to overcome these barriers. With growing evidence regarding the potential role of CUR in PCOS treatment, we decided to provide an updated summary of the recent literature from clinical and preclinical studies on this topic.

Addressing infectious conditions presents a formidable challenge, primarily due to the escalating issue of bacterial resistance. This, coupled with limited financial resources and stagnant antibiotic research, compounds the antibiotic crisis. Innovative strategies, including novel antibiotic development and alternative solutions, are crucial to combat microbial resistance. Nanotherapeutics offers a promising approach to enhance drug delivery systems. Integration into lipid-based nanoscale delivery systems, particularly through therapeutic substance encapsulation in liposomal carriers, significantly prolongs drug presence at infection sites. This not only reduces toxicity but also shields antibiotics from degradation. Lipidic carriers, particularly liposomes, exhibit remarkable specificity in targeting infectious cells. This holds great promise in combating antimicrobial resistance and potentially transforming treatment for multi-drug resistant infections. Leveraging liposomal carriers may lead to breakthroughs in addressing drugresistant bacterial infections. This review emphasizes the potential of antimicrobial-loaded liposomes as a novel delivery system for bacterial infections. Encapsulating antimicrobial agents within liposomes enhances treatment efficiency. Moreover, liposomal systems counteract challenges posed by antimicrobial resistance, offering hope in managing persistent multidrug-resistant infections. In the battle against bacterial resistance and the antibiotics crisis, the use of antimicrobial-loaded liposomes as delivery vehicles shows great promise. This innovative approach not only extends drug effectiveness and reduces toxicity but also provides a path to address highly resistant infectious conditions. As research advances, liposomal nanotherapeutics may emerge as a transformative solution in the fight against bacterial infections.

Background: Tyrosine kinase inhibitors (TKIs) target certain cell signalling pathways, and have become a promising class of medications for the treatment of cancer in recent years. Because of their distinct structure and adaptable chemistry, pyrazolines have drawn a lot of interest from organic and medicinal chemists. Their exceptional TKI activity has prompted them to investigate chemotherapy for cancer.

Objective: We aim to develop agents that inhibit tyrosine kinases highly effective with the least amount of harm possible, perhaps improving the course of cancer treatment.

Methods: This review compiled current information from recent literature sources, includ-ing in vitro, in vivo, approved medications, active clinical trials, and the structure-activity relationships (SAR) linked to various pyrazoline analogues used as small-molecule Tyro-sine Kinase Inhibitors in cancer treatment.

Results: This study focuses on SAR inside the pyrazoline ring and its derivatives as TKIs, and it emphasizes current developments, including patents, authorized medications, and compounds in clinical trials.

Conclusion: By enhancing our understanding of these compounds, our goal is to aid in making the roles of pharmacologists, scientists, and researchers who are designing and developing next-generation anticancer drugs with pyrazoline scaffolds easier. The future holds immense potential for the continued evolution of pyrazoline-based therapies, offer-ing renewed hope in the ongoing battle against cancer.

Nuclear factor erythroid 2-related factor 2 (Nrf2) is a regulator of the cellular antioxidant defense system that plays an important role in reducing the risk of various pathophysiological conditions, including cancer. Targeting Nrf2 presents an attractive therapeutic approach to overcome these challenges and improve cancer treatment outcomes. Nanoparticles, with their unique physicochemical properties, offer several advantages over conventional therapies for targeting Nrf2. These include enhanced stability, improved permeability and retention effect, and precise targeting capabilities. Moreover, delivery systems based on nanotechnology have shown promise in overcoming the limitations of conventional cancer therapies, including ineffective precision targeting and momentous complications. The therapeutic efficacy of Nrf2 inhibitors may be enhanced by using nanoparticles for specific drug targeting and deeper tissue penetration. This involves optimizing nanoparticle formulations, understanding their interactions with the biological environment, and ensuring their safety and biocompatibility. Effective nanoparticle formulations are being developed to transport Nrf2 inhibitors, which can significantly improve treatment outcomes and address the limitations of conventional cancer therapies. Further studies are needed to explore the potential of nanotechnology in targeting Nrf2 for cancer therapeutic purposes.

Introduction: Leishmaniasis is an affliction caused by the protozoan parasites of the Leishmania genus. This disease impacts a substantial global populace, exceeding one million individuals, leading to disability-adjusted life years and fatalities, particularly within tropical regions. At present, the existing drug therapies have not attained a degree of efficacy that can be unequivocally classified as genuinely triumphant. In this context, the conception of novel compounds possessing the capacity to impede the parasite's life cycle at various stages holds considerable significance.

Methods: In this research endeavor, an exploration was undertaken involving the design and synthesis of nineteen derivatives incorporating the nitrovinyl pharmacophore. The subsequent evaluation of their impacts on L. major was conducted through a combination of in vitro (amastigote and promastigote inhibition) and in silico (molecular docking) investigations.

Results: All of the compounds were synthesized and purified with good yields. In the amastigote inhibition assay, compounds 10, 15, and 18 showed better inhibitory effects than the standard drug meglumine antimonate (MA). Regarding the synergistic impact of synthesized compounds and MA together, all outcomes were significantly better than those of monotherapy of each in amastigote and macrophage forms. In the promastigote assay, compounds 2, 8, 12, 15, 16, 17, and 19 demonstrated superior inhibitory effects compared to MA. Moreover, compounds 4, 12, and 15 showed the best synergies with MA in inhibiting amastigotes. According to docking scores, 1XTP (a SAM-dependent methyltransferase) and 4G5D (Prostaglandin F synthase) receptors were found to be the most probable targets in their mechanism of action.

Conclusion: In vitro evaluations and computational analyses strongly suggest that these compounds could be effective against both L. major amastigotes and promastigotes. Additionally, they exhibited notable synergistic interactions with MA against both living forms of the parasite.